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3657 Using Circulating Tumor DNA to Spare Patients with DLBCL Unnecessary Treatment and Cost: A Model-Based Analysis

Program: Oral and Poster Abstracts
Session: 902. Health Services and Quality Improvement: Lymphoid Malignancies: Poster II
Hematology Disease Topics & Pathways:
Clinical Practice (Health Services and Quality), Health outcomes research
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Edward R Scheffer Cliff, MBBS, MPH1,2, David A Russler-Germain, MD, PhD3 and Amar H. Kelkar, MD, MPH, FACP4,5

1Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia
2Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
3Siteman Cancer Center, Division of Oncology, Washington University School of Medicine, Saint Louis, MO
4Department of Medicine, Division of Hematology & Oncology, Harvard Medical School, Boston, MA
5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

Introduction

Despite its advantages, 18F FDG positron emission tomography (PET) can yield false positives in diffuse large B cell lymphoma (DLBCL), potentially putting patients at risk of overtreatment. This was seen in long-term follow-up of the GOYA trial, where >50% of patients who did not achieve complete remission on end of treatment (EOT) PET following first line chemoimmunotherapy remained alive and progression-free many years later. Similar outcomes were seen in CALGB 50303.

Plasma derived circulating tumor DNA (ctDNA) is an emerging biomarker in DLBCL. PhasED-Seq is a ctDNA assay that requires recovery of multiple variants on the same single strand of DNA, and thereby offers improved specificity for determining true disease activity.

Chimeric antigen receptor T-cell (CAR-T) therapy has improved survival in primary-refractory and early relapsed DLBCL compared to conventional salvage chemotherapy and autograft, but has substantial therapeutic and financial toxicities that warrant judicious utilization.

We therefore modeled an EOT ctDNA-guided strategy for patients with DLBCL completing frontline therapy, focused on those who are EOT PET positive to reduce potential CAR-T overtreatment.

Methods

We used a decision tree model to compare current practice with potential future treatment algorithms that incorporate ctDNA testing to guide treatment decision making for DLBCL following completion of frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). The model was built using TreeAge Pro Healthcare 2024.

The standard care paradigm includes an EOT PET, where PET-positive cases receive either empiric second line therapy, biopsy, or repeat PET scan, with biopsy positive or repeat PET positive cases receiving second line CAR-T with axicabtagene ciloleucel (axi-cel).

In the intervention strategy, only patients with positive EOT PET results received ctDNA testing, using the PhasED-Seq assay based on published performance metrics. Patients with positive ctDNA results were deemed to have active DLBCL, and thus received CAR-T. PET-positive, ctDNA-negative patients were not treated unless their disease progressed.

To evaluate secondary cost outcomes, we performed a cost-minimization analysis from a health system perspective to evaluate direct medical costs. The model included cost of PET scans, biopsies, CAR-T (including supportive care, hospitalizations, and associated clinic visits), and ctDNA testing. Event probabilities and cost data were derived from a combination of recent publications, conference presentations, and Medicare procedure pricing. Since pricing for ctDNA testing by PhasED-Seq is not yet available, we estimated a base case price of $5,000 per test.

Results

In our model, an EOT ctDNA-guided treatment strategy significantly decreased CAR-T utilization in patients with PET-positive DLBCL (from 83% to 57% of patients) and reduced overall CAR-T use (from 30% to 22% of patients). Additionally, the ctDNA strategy lowered average healthcare costs (from $139,820 to $106,273 per patient).

Sensitivity analyses showed that ctDNA guided treatment reduced CAR-T utilization in almost all circumstances, except if: 1) the probability of a patient with a positive EOT PET having negative ctDNA testing was <18% (compared to 44% in clinical data); or 2) the probability of DLBCL progression within one year with PET positivity and ctDNA negativity was >61% (compared to 4% in early clinical data).

Conclusions

Our model suggests ctDNA testing can refine diagnostic precision in DLBCL after first-line treatment, reducing CAR-T exposure for patients unlikely to benefit based on likely false positive EOT PET, thus mitigating therapeutic harm and costs. However, the lack of large-cohort data of standardized-methodology ctDNA highlights the urgent need for clinical trials investigating measurable residual disease-adapted approaches in DLBCL to both optimize clinical outcomes and ensure efficient healthcare spending.

Disclosures: Russler-Germain: AstraZeneca: Consultancy; Regeneron: Consultancy; Genentech: Research Funding.

*signifies non-member of ASH